Process for the manufacture of unsaturated lactones of the cyclopentanopolyhydrophenanthrene series



Patented Mar. 4, 1947 PROCESS FOR THE MANUFACTURE OF UN- SATURATED LACTONES OF THE CYCLO- PENTANOPOLYHYDROPHENANTHRENE SERIES Leopold Ruzicka, Zurich, Switzerland, assignor to Ciba Pharmaceutical Products, Inc, Summit,

N. J., a corporation No Drawing. Application May 20, 1942, Serial No. 443,840. In Switzerland July 11, 1941 Claims. 1

The cardio-active substances, both of the digitalis and strophanthus series and of the squill and toad-poison group, are unsaturated lactones of the cyclopentanopolyhydrophenanthrene Series.

It has now been found that similar unsaturated lactones of the cyclopentanopolyhydrophenanthrene series can be obtained, iflactones of this series which are saturated in the lactone ring and contain a substituent X in the oc-, V- or B-position to the carbonyl of the lactone, group, or on the carbon atom Ito which the .lactone group is attached, are treated with'agents which cause elimination of HX, X representing a free hydroxyl group, a group which upon hydrolysis is converted into a hydroxyl group, a thiol group or an amino roup.

The lactones used as starting materials may be saturated or unsaturated in the cyclopentanopolyhydrophenanthrene =radical, be substituted anywhere and be of any configuration. The radical mentioned may further be attached c y to a carbon atom-of the lactone ring or may be connected to same through a branched or ,unbranched aliphatic chain. The lactone ring may have, apart fromzthe substituent containing the steroid nucleus and possibly the substituent .21, one or more alkyl or aryl groups.

The'following may be given asexamples cf the 1 substituent X, which is to beeliminated: free,

esterified or etherified hydroxyl groups, and, more particularly, halogen or-pseudo-halogen atoms, amino groups, free or substituted by alkyl, aryl or other radicals, and free or substituted ihiol groups. The substituents to be eliminated can be for example in the -c-,'*/ .or 6-position to the carbonyl of the lactone grouping, either in the lactone ring itself, on the carbon atom of the steroid structure which bears this'ring or in a chain connecting the two ring systems.

Suitable starting products are obtained, for

example, by brominatio-n of the corresponding saturated lactone e, g. the M-E-acetoxydl-hydroxy-norcholenic acid lactone or itshydrogenation product, whereby the bromide atom obviously enters the c-position to the carbonyl group. Other starting products maybe obtained, for example,

fromoxide such as vinyl androstane oxide, .etc.

which can be easily obtained in the known Way from vinyl-androstenediol, allyl-androstenediol and similar compounds. If these oxides are caused to react with malonic ester or substituted malonic esters and analogous compounds such as cyano- 'acetic acid, saturated hydroxy-lactones are obtained after decarboxylation which can be converted by the present process into unsaturated lactones. These hydroxy-lactones correspond to the following formulas:

(I)H CHCH The elimination of the. hydroxyl or substituted hydroxyl group is best carried out by known methods such as, for example, the action of acids, acid salts or substances which lower the surface tension, if necessary at increased temperature and with simultaneous distillation or sublimation. In a similar known way free and substituted thiol and amino groups are eliminated. The last named groups can be removed, for example, by conversion to quaternary ammonium bases and treatment with alkalies. Alkaline media, particularly tertiary'amines also serve to remove the hydrogen halide from the halogenized lactones; the other known methods may, however, also be utilized.

The unsaturated lactones obtained as endproducts are identical with the natural cardioactive genins or have a similar structure.

Example 1 From the compound C25H36O4, which is presumably a 3-acetoxy-17-hydroxy-norcholenic acid lactone (see Mieschen8z-Fischer, Helv. Chim. Acta. vol. 22, p. 157 [1939]), a bromo-lactone is prepared by the action of 2 mols. bromine and subsequent elimination of the'bromine atoms in the 5,6-po-sition e. g. by means of alkali iodide in acetone. 3 gr. of this starting product are boiled with 20 gr. diethyl-anlline until the hydrogen bromide is completely eliminated. The reaction mixture is then poured into water, extracted with ether and shaken up with acid. The ether solution is evaporated down, the crude product puried first by acetylation with acetic anhydride and pyridine and then by chromatography over alupiperidine, the p z'y-lactone can be converted into minimum oxide. On washing, the majority is found in the benzene-ether fraction and can be further purified by recrystallisation from alcohol. The compound presumably has the constitution of a A -3-acetoxy-17-hydroxy-norchola- 5 dienic acid lactone.

The same unsaturated lactone is obtained if the bromo-lactone is first converted to an aminolactone with amines, and the amino group then eliminated by heating or treating with acids. The 10 corresponding thiol-lactone (prepared by treating the bromo-lactone mentioned above with sodium hydrosulphide) can also be used instead of the amino-lactone.

Example 2 'y' [A -3hydroXy-etio-cholenyl (17 ]-'y' -oxo-nbutyric acid of the formula:

CH3 CH3 Y! 5! ---C 0-CH2-C H2-C 001-1 20 D i .0 l .5

(obtained by the action of malonic ester on 21- romo-pregnene-3-ol-20-one, saponification and decarboxylation) is converted with acetic anhydride and a trace of acetyl chloride into 'y-[A -3- acetoxy-etio-cholenyl-(17 l-y-acetoxy butyrolactone of the formula:

CH3 CH3 QCQGH3 C-(|3Hz /CH2 00 I omcoo 5 gr. of this substituted v-hydrcxy-lactone are distilled in a high vacuum. A mixture of 'y'-[A 3-acetoxy etio cholenyl '7)]-A"'= '-butenolide and 'y-EA -3-acetoxy-etio-cholenyl -(1'I) ]-A'="'- butenolide, having the following formulas, is obtained with elimination of acetic acid:

CH3 CH:

(B\ /OH2 00 and .1

CH3 CH3 cH-fiH t /CH co CHzCOO- 5 The two unsaturated lactones can be separated by the usual methods, e. g. by chromatography. By heating in the presence of catalysts e. g.

the mud-lactone.

The same lactones may be obtained from -[A -3-acetoxy etio cholenyl-(1'7) l v-chlorbutyro-lactone (obtainable as above with the use of acetyl chloride alone).

If one starts with '-[A -3-acetoxy-etio-cholenyl-(l?) -ch1or-a' methyl butyro lactone (obtained as above, but using methyl malonic ester instead of malonic ester) 'y'-[A -3-acetoxyetio-cholenyl- (17) l-u-methyl-A -butenolide is obtained in addition to the corresponding A lactone.

Example 3 6'-[A= -3hydroxy-etio cholenyl -(17) ]-6-oxon-valerianic acid (obtained by the action of propiolic acid ester on 21-bromo-pregnene-3-ol-20- one, hydrogenation of the acetylene linkage and saponification) are converted, by heating with acetyl chloride into 6-[M-3-acetoxy-etio-cholenyl-(l'?)]-6'-chlor-6-pentanolide of the following formula:

CHaCO0- 2 gr. of this chloro-lactone are boiled for a short time with 5 gr. pyridine. The reaction mixture is poured into water, the substance extracted with ether and washed with dilute acetic acid. The substance is purified by sublimation in a high vacuum. The product is 5-[A -3-acetoxyetio-cholenyl-(l'l) l-B'zM-pentenolide of the formula:

CH3 CH3 If 6'-[A -3-acetoxy etio-cholenyl (17)] 6'- chloro-A'=""-pentanolide (obtained as above after partial hydrogenation of the acetylene linkage) is treated in a similar way, 6-[A -3-acetoxy-etiocholenyl-(17) l-pentadieneolide is obtained as end-product. It has the following formula:

CH1 CH3 CH p CO CHaCOO The lactones described can be converted by hydrolysis into the corresponding 3-hydroxy compounds.

What I claim is:

1. A lactone of the group consisting of the saturated and unsaturated fiveand six-membered lactones which are substituted at the w-carbon atom by a A -3-acyloxy-etio-cholenyl-(17) radical.

2. A 'y-[A -3-acetoxy-etio-cholenyl (1'7) l-A butenolide, m representing one Of the positions a :c and B :7 of the lactone ring.

3. A 7-[A -3-acetoxy-etio-cholenyl (1'7) l-a' methyl-A -butenolide, 3: representing one of the positions oa'ifl' and B'Z'y of the lactone ring.

6 4. The 6'-[A -3-acetoxy-etio cholenyl (17) 6' '-penteno1ide of the formula REFERENCES CITED CH1 CH: CH The following references are of record in the file of this patent: 5

5 UNITED STATES PATENTS Number Name Date A 2,265,165 Hopfi et a1. Dec. 9, 1941 2,359,096 Elderfield Sept. 26, 1944 K 10 2,153,700 Serini Apr. 11, 1939 2,247,822 Schwenk July 1, 1941 5. The 6'-[A5-3 acetoxy etio cho1eny1-(17) 2,249911 Oppenauer J ly 22, 1941 p tad d of t u a 2,188,330 Bockmuhl Jan. 30, 1940 CH3 CH3 on 2,184,299 Hildebrandt Dec. 26, 1939 15 OTHER, REFERENCES 5 r! Fieser, Chemistry of Natural Products Related to Phenanthrene (1936), 262-269-312-313. N Linville and Elderfield, Journal Organic Chem- 1 2o istry, 1941, pp. 270-272; CHaOOO Helvetica, Chimica Acta, Vol. XXIV, Feb. 1,

1941, pp. 76-82. LEQPOLD RUZICKA. 

